Received: 10 July 2020

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Revised: 24 May 2021

DOI: 10.14814/phy2.14932

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Accepted: 25 May 2021

ORIGINAL ARTICLE

Blood glucose concentration is unchanged during exposure to
acute normobaric hypoxia in healthy humans
Jason S. Chan1 | Alexandra E. Chiew1 | Alexander N. Rimke1 | Garrick Chan1 |
Zahrah H. Rampuri1 | Mackenzie D. Kozak1 | Normand G. Boulé2 | Craig D. Steinback2
Margie H. Davenport2
| Trevor A. Day1
1

Department of Biology, Faculty of
Science and Technology, Mount Royal
University, Calgary, AB, Canada
2

Alberta Diabetes Institute, Faculty of
Kinesiology, Sport, and Recreation,
University of Alberta, Edmonton, AB,
Canada
Correspondence
Trevor A. Day, Department of Biology,
Faculty of Science and Technology,
Mount Royal University, 4825 Mount
Royal Gate SW, Calgary, AB, T3E 6K6,
Canada.
Email: tday@mtroyal.ca
Funding information
Funding and support were provided
by the MRU Faculty of Science and
Technology a Natural Sciences and
Engineering Research Council of Canada
(NSERC) Discovery grant (TAD;
RGPIN-­2016-­04915).

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Abstract
Normal blood [glucose] regulation is critical to support metabolism, particularly in
contexts of metabolic stressors (e.g., exercise, high altitude hypoxia). Data regarding
blood [glucose] regulation in hypoxia are inconclusive. We aimed to characterize
blood [glucose] over 80 min following glucose ingestion during both normoxia and
acute normobaric hypoxia. In a randomized cross-­over design, on two separate days,
28 healthy participants (16 females; 21.8 ± 1.6 years; BMI 22.8 ± 2.5 kg/m2) were
randomly exposed to either NX (room air; fraction of inspired [FI]O2 ~0.21) or HX
(FIO2 ~0.148) in a normobaric hypoxia chamber. Measured FIO2 and peripheral oxygen saturation were both lower at baseline in hypoxia (p < 0.001), which was maintained over 80 min, confirming the hypoxic intervention. Following a 10-­min baseline
(BL) under both conditions, participants consumed a standardized glucose beverage
(75 g, 296 ml) and blood [glucose] and physiological variables were measured at
BL intermittently over 80 min. Blood [glucose] was measured from finger capillary
samples via glucometer. Initial fasted blood [glucose] was not different between trials
(NX:4.8 ± 0.4 vs. HX:4.9 ± 0.4 mmol/L; p = 0.47). Blood [glucose] was sampled
every 10 min (absolute, delta, and percent change) following glucose ingestion over
80 min, and was not different between conditions (p > 0.77). In addition, mean, peak,
and time-­to-­peak responses during the 80 min were not different between conditions
(p > 0.14). There were also no sex differences in these blood [glucose] responses in
hypoxia. We conclude that glucose regulation is unchanged in young, healthy participants with exposure to acute steady-­state normobaric hypoxia, likely due to counterbalancing mechanisms underlying blood [glucose] regulation in hypoxia.
KEYWORDS

acute hyperglycemia, acute hypoxia, blood [glucose] regulation, insulin sensitivity

This is an open access article under the terms of the Creat​ive Commo​ns Attri​bution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society
Physiological Reports. 2021;9:e14932.		
https://doi.org/10.14814/phy2.14932

wileyonlinelibrary.com/journal/phy2

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IN T RO D U C T IO N

Blood glucose concentration is tightly regulated through well-­
established mechanisms, which are essential for maintaining
metabolic homeostasis. Many factors, including carbohydrate ingestion, exercise, stress, and environmental conditions may affect glucose regulation in humans (Ahlborg et al.,
1974; Kamba et al., 2016; Larsen et al., 1997). Responses to
these factors are important for the maintenance of metabolic
homeostasis, and serious consequences may result following
significant acute or chronic changes in glucose regulation,
such as metabolic diseases.
The ingestion of carbohydrates and subsequent absorption
into the bloodstream results in a temporary rise in blood glucose. Normally, this rise in blood glucose is associated with
a concomitant rise in insulin, released from pancreatic beta
cells, lowering blood glucose again via uptake, utilization,
and/or storage of glucose in tissues (Salunkhe et al., 2016). In
hypoxic environments, where oxygen availability is reduced,
there is a shift toward a higher proportion of glucose metabolism (Goto et al., 2015), possibly affecting basal glucose and
or glucose concentration following carbohydrate ingestion,
and an increased proportion of glycolytic metabolism and
fermentation can result in accumulating lactic acid production (Lottes et al., 2015).
A number of studies using reduced animal preparations
suggest the possibility of altered glucose regulation in hypoxia, although with conflicting results. Using isolated islets
of Langerhans beta cells from rats, Ota et al. (2012) found an
attenuation of insulin secretion following 24 h of intermittent
hypoxia, which may serve to maintain blood glucose in hypoxia in vivo. Conversely, using type II alveolar cells from
rats, Ouiddir et al. (1999) found that GLUT1 transporters
were upregulated following 18 h of hypoxic exposure, potentially facilitating an increase in glucose uptake in hypoxia.
In addition, using dissected hindlimb muscles in rats, Cartee
et al. (1991) showed an increase in glucose transporter translation following 40-­min perfusion with normocapnic anoxia
(5% CO2 and 0% O2) perfusate.
Studies in humans investigating the specific effects of hypoxia on glucose concentration via interactions with insulin
release or sensitivity and/or glucose utilization or storage remain limited and lack consensus. Many studies suggest that
blood [glucose] may be increased in hypoxia, potentially
through reductions in insulin secretion or sensitivity. Braun
et al. (2001) found a reduction in insulin sensitivity in 12
women exposed to simulated 4,300 m for 16 h. Similarly, in
8 men brought immediately to 4,500 m for 7 days, Larsen
et al. (1997) found an increase in both blood insulin and
glucose in the first few days, suggesting the development
of acute insulin insensitivity. Conversely, a number of studies suggest that blood [glucose] may be decreased in hypoxia, potentially through an increase in insulin secretion or

CHAN et al.

sensitivity or increased glucose utilization. Kelly et al. (2010)
found no difference in circulating insulin levels and/or a decrease in plasma glucose concentration in eight healthy humans exposed to hypobaric hypoxia equivalent to 4,300 m
for 120 min. In 12 men exposed to a simulated altitude of
3,000 m, using tagged glucose and positron emission tomography, Chen et al. (2009) found an increase in plasma lactate
levels and increased glucose uptake in cardiac muscle, but
not skeletal muscle, brain or liver, suggesting the potential
for differential mechanisms in glucose homeostasis in between tissues. In addition, Morishima and Goto (2014) found
no differences in blood glucose or insulin concentrations in
eight men exposed to an FIO2 of 14% over 7 h. These studies suggest that the mechanisms underlying the regulation of
blood [glucose] may be counterbalanced, leaving [glucose]
unchanged in hypoxia in humans (Morishima & Goto, 2014).
Given the low number of participants utilized in these
limited number of previous studies in humans, in addition
to the disparate findings and current lack of consensus regarding the mechanisms and effects of hypoxia on blood
[glucose], we aimed to characterize the possible interaction
between acute normobaric hypoxia and [glucose] following a
standardized oral glucose beverage (75 g glucose in 296 ml)
in a large number of healthy human participants. Specifically,
we hypothesized that blood [glucose] over 80 min following
acute glucose ingestion would not be significantly different
between acute steady-­state normoxia and hypoxia conditions.

2
2.1

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M ATERIAL S AND M ETHOD S

| Ethics and participant recruitment

Ethics approval was obtained in advance from the Mount
Royal University Human Research Ethics Board (Protocol
2016-­91). This study abided by the Canadian Government
Tri-­
Council Policy on Research Ethics Policy Statement
(TCPS2) and the Declaration of Helsinki, except for registration in the database. Participants were recruited for the experiment through word of mouth, and participants read and
signed a consent form which included information on the
study and risk information, a demographic form, which was
used to record basic participant information (e.g., weight,
height, and age) and confirms the lack of self-­reported medical conditions (e.g., respiratory, cardiovascular and metabolic). Participants had a body mass index (BMI) that fell
within a healthy range of 20–­25 kg/m2, were non-­smokers,
and did not ingest any prescription medications, with the exception of oral contraceptives. No participants had been to
altitude in the previous year and were residents of Calgary
(1,130 m). Biological sex differences were not an a priori
component of the study design in advance, and the ovarian
cycle was not accounted for in our female participants.

   

CHAN et al.

2.2

| Equipment and measurements

The Hypoxico Altitude Training System (Hypoxico, Inc.)
complete with a small portable tent-­style chamber and nitrogen concentrator was used to simulate hypoxic conditions by
displacing oxygen within the chamber, increasing the fraction of inspired nitrogen. Two participants at a time were
seated inside the semi-­sealed chamber in chairs, with a small
table between them for reading material/computers and use
of portable devices (see below). A portable oxygen analyzer
(MAXO2ME model R213P65, Maxtec) was used to detect
and measure the fraction of inspired oxygen (FIO2) inside of
the tent to ensure accuracy of the targeted level of oxygen
during each trial. Chamber temperature was measured using
a digital thermometer inside the chamber (VWR, Traceable
Digital Thermometer), and recorded manually.
Blood [glucose] measurements were obtained using a
standard capillary draw using sterile lancets and measured
with an Accu-­Chek Aviva (Roche Diabetes Care) device with
glucometer sensor strips. Trained investigators utilized capillary samples by asking participants to slip their hand out
of the tent-­style hypoxic chamber (through an open zipper)
for the ease of capillary sampling by a trained investigator
positioned outside the chamber, for a total of nine separate
samples per participant, per trial. After participant training,
resting heart rate (HR) and peripheral blood oxygen saturation (SpO2) were measured by participants inside the chamber (PureSAT model 7500 pulse oximeter, Nonin Medical,
Inc.). A single arterial blood pressure value was obtained
using an automated brachial blood pressure cuff (Omron
Healthcare), with mean arterial pressure calculated as 2/3
diastolic +1/3 systolic. In a subset of participants (n = 16),
steady-­state pressure of end-­tidal CO2 (PETCO2) was measured with a portable capnometer (Masimo, EMMA). For
all measures at all time points, these measures represent a
single measurement per participant. Participants were monitored through a window in the tent, and instructions were
relayed to participants as required. For participant safety, participants were also provided with sheets with the Lake Louise
acute mountain sickness (AMS) scoring system (Roach et al.,
1993), and asked to report any acute AMS symptoms to investigators at each measurement time-­point.

2.3

| Experimental protocol

Participants were recruited for a large, within-­
individual
cross-­over design study to compare the effects of normoxic
and steady-­state hypobaric hypoxia on blood [glucose] over
80 min. On separate days, separated by at least 2 days, the
control and experimental protocols were randomized for
each participant. Participants visited the lab in a fasted state,
having been instructed to avoid strenuous exercise (e.g.,

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Knudsen et al., 2014) and caffeine and food for at least 12 h
prior to beginning the experiment, which took place before
noon on the testing day.

2.3.1

| Normoxic conditions

For the hypoxic trial, the nitrogen concentrator was running but
not connected to the hypoxia tent. This arrangement provided a
normoxic condition, with the participant breathing room air at
an altitude of ~1,130 m (PATM O2 ≅ 140 mmHg, FIO2 = 0.209
of 669 mmHg in Calgary). Each participant was seated inside
the semi-­sealed hypoxia chamber and underwent a 10-­min
baseline measurement, where HR, SpO2, BP, PETCO2, and
blood [glucose] values were obtained. The participant was
then allowed up to 5 min to ingest a standard glucose beverage
(75 g, 296 ml, Trutol). After ingestion, the participant remained
seated in the hypoxia tent for an additional 80 min, where glucose values were obtained every 10 min between 5 and 10, 15
and 20, 25 and 30, 35 and 40, 45 and 50, 55 and 60, 65 and 70,
and 75 and 80-­min post-­glucose ingestion. FIO2 was monitored
continuously every 5 min during the 80-­min period. SpO2, HR,
MAP, and PETCO2 values were obtained at 10, 20, 30, 40, 50,
60, 70, and 80-­min post-­glucose ingestion.

2.3.2

| Hypoxic conditions

The above protocol was replicated under hypoxic conditions. The nitrogen concentrator was used to achieve the
hypoxic conditions in the tent, which was monitored and
equivalent to an altitude of ~4,100 m (PATM O2 ≅ 100 mmHg,
~FIO2 = 0.148–­0.15 of 669 mmHg in Calgary; ~1,130 m).
SpO2 was monitored continuously for safety and did not fall
below 80% in any participant in any trial.

2.4

| Data and statistical analysis

The values obtained from both the control protocol (normoxia) and experimental protocol (hypoxia) are presented as
mean values ± standard deviation (SD). Statistical significance was assumed at p < 0.05 Systat SigmaPlot (v. 14).
A paired t test was performed on mean values to compare
data from the baseline period during both normoxia and hypoxia and trials for the following variables: FIO2, SpO2, HR,
MAP, and fasted blood [glucose] (Table 1).
Two factor repeated-­
measures ANOVAs (factor one:
time, factor two: oxygen condition) were performed to assess potential differences in FIO2, SpO2, HR, and MAP for
each gas trial (i.e., normoxia and hypoxia) to assess potential
changes in these variables over the protocol duration in each
trial (Figure 1). Where significant F ratios were detected, a

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CHAN et al.

T A B L E 1 Normoxia versus hypoxia intervention and participant
baseline data recorded at the end of a 10-­min baseline in both
normoxic and hypoxic conditions
Variable/Condition

Normoxia

Hypoxia

PATM (mmHg)

~669

~669

FIO2 (%)

20.4 ± 0.4

14.8 ± 0.6a

PATM O2 (mmHg)

~140

~100

PIO2 (mmHg)

~130

~92

SpO2 (%)

96.8 ± 2.2

88.6 ± 3.7a

HR (min−1)

72.0 ± 11.3

79.0 ± 8.9a

MAP (mmHg)

86.8 ± 8.0

88.2 ± 7.6

Fasted BG (mmol/L)

4.8 ± 0.4

4.9 ± 0.4

Note: PATM, atmospheric pressure in the lab. FIO2, fraction of inspired O2 (%;
measured). PATM O2, atmospheric O2 pressure (PATM × FIO2). PIO2, pressure
of inspired O2 ((PATM –­ 47) × FIO2). SpO2, peripheral oxygen saturation (%;
measured). HR, heart rate (min−1). MAP, mean arterial pressure (mmHg;
measured). BG, blood glucose (mmol/L; measured). Values are reported as
mean ± SD.
a

Denotes significant difference from normoxia for that variable (p < 0.001).

Student–­Newman–­Keuls post hoc test was utilized for pair-­
wise comparisons.
Two factor repeated-­measures ANOVAs (factor one: time,
factor two: oxygen condition) were performed to assess potential differences in blood [glucose] between normoxic and
hypoxic conditions. Where significant F ratios were detected,
a Student–­Newman–­Keuls post hoc test was utilized for pair-­
wise comparisons. These comparisons were carried out on
absolute, delta from baseline, and percent change from baseline measures (Figure 2).
Paired t tests were utilized to compare the 80-­min average
and absolute peak value of blood glucose (wherever it occurred) between hypoxia and normoxia. In addition, a paired
t test was performed to compare the time-­to-­peak glucose
concentration between hypoxia and normoxia (Figure 3).
To assess the potential relationship between SpO2 and
absolute peak blood [glucose], we performed a Pearson
product-­moment correlation between the peak glucose concentration in hypoxic conditions (wherever it occurred) and
the corresponding SpO2 at that time point.
Last, to assess potential sex differences in [glucose] regulation in hypoxia, we utilized unpaired t tests to assess differences in mean, peak, and time-­to-­peak [glucose] in hypoxia
between males and females.

3
3.1

|

R E S U LTS

| Baseline values

Twenty-­eight participants (16 females; 21.8 ± 1.6 years;
BMI 22.8 ± 2.5 kg/m2) completed the experiment in both

randomized, within-­
individual, cross-­
over normoxic, and
hypoxic conditions for a total of 56 trials. Baseline measurements for FIO2, SpO2, HR, MAP, and blood glucose were
taken for each trial (Table 1). As expected, FIO2 and SpO2
were significantly lower in hypoxia compared to normoxia
(p < 0.001), confirming the steady-­state hypoxic conditions.
HR was significantly higher in hypoxia compared to normoxia (p < 0.001), confirming the hypoxic stimulus throughout. However, MAP and fasted blood [glucose] were not
significantly different between hypoxic and normoxic trials
(p = 0.33 and p = 0.47, respectively). Participants did not
report any AMS symptoms in either trial.

3.2

| Environmental measurements

FIO2 decreased mildly but significantly from 20.4 ± 4.5% to
19.8 ± 4.5% during the 80-­min normoxic trial (p < 0.001) but
remained stable between 14.8 ± 0.6% and 15.0 ± 0.54% in
the hypoxic trial (Figure 1a), confirming the hypoxic stimulus throughout. Under normoxic and hypoxic conditions, the
chamber temperature was significantly higher at 80 min compared to baseline. Under normoxic conditions, the chamber
temperature increased from 24.6 ± 1.5°C to 26.5 ± 1.5°C
(p < 0.01), while under hypoxic conditions, the temperature
increased from 25.4 ± 1.5°C to 27.0 ± 1.5°C (p < 0.01; data
not shown).

3.3 | Respiratory and cardiovascular
measurements
Under normoxic conditions, PETCO2 at 80 min was significantly higher (36.4 ± 8.9 mmHg) compared to baseline
(31.8 ± 2.3 mmHg; p = 0.03), confirming a slight accumulation of chamber CO2. Under hypoxic conditions, PETCO2 at
80 min was not significantly different at 30.8 ± 6.4 mmHg
compared to normoxia 29.4 ± 4.0 mmHg (p = 0.29), suggesting the airflow from the nitrogen concentrator helped wash
out metabolically derived CO2 in the chamber (PETCO2 data
not shown).
SpO2 was significantly higher in normoxic and hypoxic
conditions throughout 80 min, confirming the hypoxic stimulus throughout (p < 0.001; Figure 1b). Although the SpO2
was stable across 80 min in the normoxic trial, it did increase
significantly in the hypoxic condition by 70–­80 min (interaction: p = 0.006). HR was higher in hypoxic than normoxic
conditions throughout 80 min, suggesting a sympathetic
response to hypoxia (p < 0.001; Figure 1c). However, HR
increased significantly under both normoxic and hypoxic
conditions over 80 min (p < 0.001). There were no differences in MAP between trials initially (p = 0.7; Figure 1d).
However, MAP was stable during the normoxic trial, but

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F I G U R E 1 Changes in the fraction of inspired oxygen (FIO2; %), peripheral oxygen saturation (SpO2; %), heart rate (min−1), and mean
arterial pressure (MAP; mmHg) in response to varying levels of oxygen over 80 min following glucose ingestion. The data from normoxic
(black) and hypoxic (grey) conditions collected before (BL; transparent grey box) and after a glucose load. The baseline (BL) measures were
obtained following 10 min in the chamber in each oxygen condition, but were fasted (transparent grey box). Participants then consumed the
75 g glucose beverage, under both oxygen conditions (see Figure 2). (a) Mean FIO2 values at baseline were lower in hypoxia (14.8 ± 0.6%)
compared to normoxia (20.4 ± 0.5%; Table 1), and stable throughout the 80-­min protocol. (b) Mean SpO2 values at baseline were lower in
hypoxia (88.6 ± 3.7%) compared to normoxia (96.8 ± 2.2%; Table 1). SpO2 values were stable throughout the 80-­min protocol in normoxia,
but significantly higher than baseline during the hypoxia protocol. (c) Mean heart rate (HR) values at baseline were higher in hypoxia
(79.0 ± 8.9 min−1) compared to normoxia (72.0 ± 11.3 min−1; Table 1). HR significantly increased from baseline in both normoxia and hypoxia
trials. (d) Average MAP values at baseline were not different between hypoxia (88.2 ± 7.6 mmHg) and normoxia (86.8 ± 8.0 mmHg; Table 1).
MAP values were relatively stable throughout the 80-­min protocol in normoxia and hypoxia, but were significantly reduced near the end of the
hypoxia trial only. All p values for main effects (Time and Condition), and interaction (Time × Condition) indicated on each graph. *represents
values different from baseline for that (or both) oxygen condition(s) over time. Values are reported as mean ± SD

decreased significantly over the duration of the hypoxic trial
(p = 0.01).

3.4

| Blood [glucose] measurements

Although blood [glucose] increased, peaked, and then decreased again over time following oral glucose consumption,
there were no differences in absolute (interaction: p = 0.77;

Figure 2a), delta from baseline (interaction: p = 0.94; Figure
2b) or percent changes in [glucose] (interaction: p = 0.94;
Figure 2c) between oxygen conditions over the 80 min.
The 80-­min average blood [glucose] values for normoxia
and hypoxia were 7.0 ± 0.6 and 7.3 ±0.8 mmol/L, respectively (p = 0.21; Figure 3a). The absolute peak values (wherever they occurred) for normoxia and hypoxia were 8.8 ± 0.8
and 9.2 ± 1.1 mmol/L, respectively (p = 0.14; Figure 3b).
The time-­to-­peak blood [glucose] for normoxia and hypoxia

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CHAN et al.

F I G U R E 2 Blood [glucose] response at baseline and following a 75 g, 296 ml of standardized glucose beverage under both normoxic (black)
and hypoxic (grey) conditions. (a) Absolute blood [glucose] values in response to glucose ingestion were not significantly different between
normoxia and hypoxia. (b) Delta blood [glucose] values in response to glucose ingestion were not significantly different between normoxia and
hypoxia. (c) Percent change blood [glucose] values in response to glucose ingestion were not significantly different between normoxia and hypoxia.
All p values for main effects (Time and Condition), and interaction (Time × Condition) indicated on each graph. *represents values different from
baseline for that (or both) oxygen condition(s) over time. Values are reported as mean ± SD

F I G U R E 3 Average and peak blood [glucose], and time-­to-­peak [glucose] for all participants in both normoxic (black) and hypoxic (grey)
conditions. (a) 80-­min average blood [glucose] was not significantly different between normoxia and hypoxic conditions (p = 0.21). (b) Absolute
peak blood [glucose] was not significantly different between normoxia and hypoxic conditions (p = 0.14). (c) Time-­to-­peak [glucose] (from b) in
minutes were not significantly different between normoxia and hypoxic conditions (p = 1.0). Values are reported as mean ± SD. NSD, no statistical
difference

were 31.4 ± 9.7 and 31.4 ± 10.1 min, respectively (p = 1.0;
Figure 3c). Last, there was no correlation between SpO2 and
peak blood [glucose] under hypoxic conditions (r = 0.013,
p = 0.95; data not shown).
To address the possibility of sex differences in the [glucose] response in hypoxia, we compared the mean, peak, and
time-­to-­peak between males (n = 12) and females (n = 16)
during hypoxia. We found no differences in mean (p = 0.79),
peak (p = 0.82) nor time-­to-­peak (p = 0.92) [glucose] values
between males and females following glucose ingestion in
hypoxia.

4

|

D IS C U SS ION

There are conflicting reports in the literature regarding the
effects of hypoxia on mechanisms that may affect blood
[glucose]. Accordingly, we sought to clarify the possible effect of acute normobaric hypoxia on glucose concentration
in healthy humans with a larger sample size than previous

reports. We hypothesized that blood [glucose] would not be
significantly different between hypoxia and normoxia, as
there are potential competing mechanisms affecting blood
glucose regulation. The principal finding of this study is that
the blood [glucose] response to an acute oral glucose load
was not different between acute normobaric normoxic and
hypoxic conditions in young healthy individuals over 80 min.

4.1

| Hypoxia and blood [glucose]

Hypoxic conditions equivalent to altitudes greater than
4,000 m have been demonstrated to significantly lower
blood [glucose] compared to normoxia during the first
60 min following 75 g oral glucose ingestion (n = 8; Kelly
et al., 2010). Glucose uptake has also been shown to increase to match the metabolic need, decreasing blood [glucose] independent of [insulin] under hypoxic conditions
Cartee et al., 1991; Chen et al., 2009; Kelly et al., 2010;
Ouiddir et al., 1999). However, the main finding of this

   

CHAN et al.

study, in a large cohort of healthy humans, suggests that
blood [glucose] remains unchanged in acute steady-­state
hypoxia when compared to normoxia. Conversely, hypoxia
has also been shown by some studies to have inhibitory effects on insulin release and sensitivity (Braun et al., 2001;
Larsen et al., 1997), which could serve to maintain or increase blood [glucose]. One possible mechanism leading to
the inhibitory effects of hypoxia on both insulin sensitivity
and secretion is the activation of the sympathetic nervous
system. Stress hormones such as epinephrine have been
shown to inhibit insulin-­induced glucose uptake, resulting
in higher blood [glucose] (Chiasson et al., 1981). However,
Braun et al. (2001) showed that the decrease in insulin
sensitivity under hypoxic conditions was not epinephrine-­
mediated. Cortisol, another stress hormone released upon
exposure to hypoxia, is associated with a decrease in insulin secretion, possibly leading to higher blood [glucose]
(Kamba et al., 2016). Thus, the overall lack of difference
in blood [glucose] between conditions in our study may
be explained in part due to the counterbalancing action of
an increase in glucose uptake in non-­insulin-­dependent
tissues (e.g., Watson & Pessin, 2001) or glucose utilization by somatic cells, and reduced insulin secretion and/
or sensitivity, serving to maintain blood [glucose]. In addition, a study by Morishima and Goto (2014) showed (a)
an increase in metabolic rate but (b) no significant differences in blood [glucose] over 7 h at a moderate simulated
altitude (15% FIO2) following the ingestion of a 75 g oral
glucose load, similar to the present study, although with a
much lower number of participants (n = 8; Morishima &
Goto, 2014).

4.2

| Sympathetic response to acute hypoxia

The increase in HR observed over 80 min in the hypoxic trial
is likely a response to the hypoxic stressor, although there
was also an initial increase in HR in the normoxic trial. A
possible explanation for these results is the activation of the
sympathetic nervous system in response to the glucose ingestion itself (Smorschok et al., 2018; Synowski et al., 2013).
Hypoxia is known to stimulate the peripheral chemoreceptors to elicit a sympathetic chemoreflex, which leads to an
increase in HR and vascular resistance (i.e., vasoconstriction;
Steinback et al., 2009). An increase in temperature has also
been shown to increase sympathetic activation, leading to an
increase in HR (Madaniyazi et al., 2016), as does glucose
ingestion, which was recently shown to activate the sympathetic nervous system (Smorschok et al., 2018), leading to an
increase in the heart rate (Synowski et al., 2013). However,
MAP was significantly lower after 80 min in the hypoxic
trial. This is likely due to hypoxia-­
induced vasodilation
(Blitzer et al., 1996). Accordingly, the vasodilatory effect of

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hypoxia is likely greater than its effects on sympathetic activation, lowering MAP over time.

4.3

| Methodological considerations

The present study exposed participants to a normobaric hypoxic stimulus equivalent to a simulated altitude of ~4,100 m
(PATM O2 ≅ 100 mmHg, ~FIO2 = 0.15 of 669 mmHg in
Calgary; ~1,130 m) for only 80 min, shorter than a typical
clinical oral glucose tolerance test (OGTT) protocol of 2 h.
However, we do not believe that a longer duration would
have had a significant effect on these responses, in part
because participants were long past their peak blood [glucose] (occurring early at ~30 min), and Morishima and Goto
(2014) demonstrated that there were no significant changes
in glucose regulation after being exposed to hypoxia for 7 h.
However, available evidence on glucose uptake by tissues
is inconclusive regarding time course (e.g., Gamboa et al.,
2011; Heinonen et al., 2011), and thus more studies are necessary in order for definite conclusions to be drawn regarding
potential oxygen and blood [glucose] interactions. We aimed
to assess the mean and peak blood [glucose] responses to
acute hypoxia in healthy men and women, not assess the longitudinal responses in a clinical diabetic population, where
the end-­point at 120-­min OGTT are utilized. Accordingly,
we believe our protocol comparing normoxic and hypoxic
peak and mean responses over 80 min in a large number of
healthy participants addressed our experimental question on
the effects of acute hypoxia on short-­term control of blood
[glucose].
One limitation of this study was the lack of additional
measurements of associated humoral variables. Lactate, insulin, and stress hormones (e.g., epinephrine and cortisol)
were not measured, as we chose to trade off study complexity
in favor of large participant recruitment. The measurement of
plasma insulin may have confirmed the inhibitory effects of
hypoxia on insulin secretion, and the measurements of stress
hormones could suggest a mechanism resulting in an inhibitory effect on insulin secretion. Because of these limitations,
we can only speculate as to the underlying mechanisms responsible for our observations, where blood [glucose] was
unchanged between conditions. However, we believe that the
high sample size and multiple methods of analysis (i.e., absolute, delta, percent, mean, peak, and time-­to-­peak) in our
study add confidence to our conclusion that blood [glucose]
homeostasis, and likely insulin release or sensitivity, is unchanged in healthy humans exposed to acute steady-­state normobaric hypoxia.
Our participants visited the lab fasted, having avoided
strenuous exercise (Knudsen et al., 2014), caffeine, and food
for at least 12-­h prior to visiting the lab on the morning of
the testing day. However, we did not instruct participants

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|   

regarding standardizing diet the night before. Robertson et al.
(2002) demonstrated that the effects of high-­fat and high-­
carbohydrate evening meals can persist overnight, affecting
the blood [glucose] responses to an OGTT. However, they
did not detect any effects on morning glucose or insulin concentrations. Although we acknowledge this weakness in our
design, we did not observe any differences in blood [glucose]
between groups under baseline conditions, and the large
within-­participant likely minimizes any effects of high fat or
high carbohydrate meals the day before our study.
The Accu-­Chek Aviva point-­of-­care device used in the
present study utilizes the glucose-­1-­dehydrogenase method
of measuring blood [glucose]. This method differs from similar studies that use laboratory determinations of blood [glucose] with the glucose oxidase method (Kelly et al., 2010;
Morishima & Goto, 2014). However, given that our study was
being conducted under hypoxic conditions, using a method
other than the glucose oxidase method may be a strength of
our study (see Tonyushkina & Nichols, 2009). Nonetheless,
the Accu-­Chek Aviva has been assessed to be an accurate
method of measuring blood [glucose] (Tack et al., 2012), and
likely did not result in relevant inaccuracies. In addition, participants acted as their own controls, and we tracked changes
over time, within-­individuals.
The small normobaric chamber used in the protocol also
presents a limitation. The small decrease in FIO2 observed
across the 80-­min normoxic trial is most likely due to the metabolic rate of the participants, utilizing the available ambient
O2 and accumulating metabolically-­derived CO2 in the small
chamber without air circulation. In addition, the small size of
the normobaric chamber led to an accumulation of CO2 as well
as an increase in temperature inside of the chamber. Both of
these consequences likely contributed to the increases in sympathetic nervous system activation independent of the hypoxia,
as evidenced by the increase in HR over 80 min. The accumulation of CO2 was assessed through the measurement of
PETCO2, which was mildly but significantly higher over 80 min
compared to baseline in the normoxic trial. The accumulation
of the CO2 in the chamber likely augmented the hypoxic ventilatory response (e.g., Teppema & Dahan, 2010), which could
increase the relative SpO2 for the participants over 80 min.
Moreover, in the hypoxic trial, the continuous airflow from
the nitrogen concentrator likely eliminating some of the accumulating CO2, as it was replacing the chamber air. Therefore,
the PETCO2 at 80 min in the hypoxic trial was not significantly
different compared to the baseline. The small increase in SpO2
observed in the hypoxic trial over 80 min was likely due to a
hypoxic ventilatory response, in which the participants were
responding to the lower amount of O2 in the normobaric hypoxia chamber (Teppema & Dahan, 2010). However, there
was a small but a significant rise in SpO2 in the normoxic
trial suggesting that the accumulating CO2, and possibly the
increase in ambient temperature, increased ventilation in the

CHAN et al.

normoxic trial (Tsuji et al., 2019). Last, the small increase in
temperature could also result in peripheral vasodilation, which
could contribute to the slight decrease of MAP over the 80 min
in hypoxia. Thus, small normobaric hypoxia chambers come
with a number of caveats that should be considered in experimental design and interpretation of results.

4.4

| Potential significance

There is considerable controversy as to whether or not hypoxia elicits a change in the regulation of blood [glucose].
Therefore, the rationale of this study was to clarify the potential interactions between acute normobaric hypoxia and
blood [glucose] in a large number of healthy, unacclimatized
lowlanders. According to our results, the time course and
magnitude of the changes in blood [glucose] in response to a
standard oral glucose load in young healthy individuals are not
different during acute exposure to steady-­state hypoxia. This
information could be of interest for trekkers ascending to high
altitude, as it may provide insightful information regarding
nutritional requirements in chronic hypoxia, particularly with
superimposed exercise, where metabolic demand is increased.
Trekkers ascending and residing at high altitude may have to
adjust their carbohydrate intake to meet their metabolic needs,
but the extent of this requirement remains unknown.
There are also disparate findings with respect to diabetic
populations at altitude. Previous studies have demonstrated
that sustained hypoxia lowers blood [glucose] through increasing glucose utilization, which could be beneficial for people
with diabetes (e.g., Kelly et al., 2010). A study performed by
Duennwald et al. (2013) found that the exposure to intermittent
hypoxia (IH) over 1 h resulted in a reduction in blood [glucose], suggesting a potential benefit of IH to diabetic patients.
However, hypoxia may also decrease insulin sensitivity (Larsen
et al., 1997) and possibly exacerbate the danger of uncontrolled
diabetes. In addition, a previous study demonstrated that hypoxia increased blood [glucose] (Singh et al., 2014), possibly
through decreasing insulin production or sensitivity, which
may also exacerbate the negative effects of uncontrolled diabetes (i.e., hyperglycemia). In a study performed by Vera-­Cruz
et al. (2015) using hyperbaric oxygen therapy (i.e., exposure
to high PO2), fasted plasma [glucose] and glucose tolerance
to an OGTT was improved in diabetic patients, suggesting an
oxygen-­dependent effect on blood [glucose] regulation in patients with diabetes. Interestingly, with respect to high altitude
natives, Okumiya et al. (2016) found that highland natives in
Tibet living at altitudes above 3,500 m were more susceptible
to the development of glucose intolerance and diabetes, but this
result likely has a number of lifestyles (e.g., physical activity,
diet) factors contributing to it. These disparate results depend
upon the degree and mode of hypoxia, as well as the population of interest. Thus, there is a critical need for more research

   

CHAN et al.

toward understanding the potential interaction between oxygen
status and blood glucose regulation, particularly regarding the
differential patterns (e.g., intermittent, acute, sustained) and
magnitude of hypoxia, and the differential rates of diabetes in
highlander versus low lander populations (e.g., Koufakis et al.,
2019; Woolcott et al., 2015).

5

|

CO NC LUS ION S

In conclusion, in a large sample of young healthy male
and female participants, blood [glucose] in response to
standard oral glucose ingestion (75 g, 296 ml) was unchanged during exposure to acute steady-­state normobaric
hypoxia (FIO2 ~14.8%) compared to room air over 80 min,
using multiple metrics including mean, peak, and time-­to-­
peak responses.

CO M P ET ING IN T E R E STS
None declared.

ACKNOWLEDGMENTS
The authors would like to thank our participants for volunteering their time and effort for this study. Additionally, we
would like to thank Melissa Cruz for laboratory assistance
and Dr. Sarah Hewitt for helpful feedback on an early draft
of the manuscript.
AUTHOR CONTRIBUTIONS
Jason Chan, protocol design, student group leadership, data
collection, data analysis, draft manuscript writing, edited, and
approved the final manuscript; Alexandra Chiew, protocol
design, data collection, data analysis, edited, and approved
the final manuscript; Alexander Rimke, protocol design, data
collection, data analysis, edited, and approved the final manuscript; Garrick Chan, protocol design, data collection, data
analysis, edited, and approved the final manuscript; Zahrah
Rampuri, data collection, edited, and approved the final
manuscript; Mackenzie Kozak, data collection, edited, and
approved the final manuscript; Normand Boulé, intellectual
contribution, edited, and approved the final manuscript; Craig
Steinback intellectual contribution, edited, and approved the
final manuscript; Margie Davenport, intellectual contribution,
edited, and approved the final manuscript; Trevor Day, ethics, funding, lab equipment support, intellectual contributions,
protocol design, data analysis, edited, and approved the final
manuscript; The corresponding author (TAD) confirms that all
coauthors have reviewed and approved of the manuscript prior
to submission.
ORCID
Craig D. Steinback https://orcid.
org/0000-0001-7190-7046

| 9 of 10

Margie H. Davenport https://orcid.
org/0000-0001-5627-5773
Trevor A. Day https://orcid.org/0000-0001-7102-4235
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How to cite this article: Chan, J. S., Chiew, A. E.,
Rimke, A. N., Chan, G., Rampuri, Z. H., Kozak, M.
D., Boulé, N. G., Steinback, C. D., Davenport, M. H.,
& Day, T. A. (2021). Blood glucose concentration is
unchanged during exposure to acute normobaric
hypoxia in healthy humans. Physiological Reports, 9,
e14932. https://doi.org/10.14814/​phy2.14932